In the United States, 400,000 infants are born preterm each year resulting in an infant mortality rate that is worse than 26 other economically developed countries in the world. Preterm birth (PTB) risk is not evenly distributed throughout American society, resulting in massive racial disparities with black women having 50% higher risk than white women. It is widely accepted that genetic variation does not explain racial differences in PTB risk, hence other biological factors must have some obligatory role for disparities in PTB. Extensive work from the Human Microbiome Project (HMP) has provided key information for women?s reproductive health, and specifically has characterized the composition of the microbial communities that occupy the cervicovaginal (CV) space. Comprehensive studies in non-pregnant women have led to the classification of CV microbial communities into community state types (CSTs). Subsequent research has demonstrated that select CSTs are associated with various pathologies such as sexually transmitted infections, bacterial vaginosis, and urinary tract infections. Yet, the data on the association of these CSTs with spontaneous PTB (sPTB) has been limited with existing studies confounded by small sample sizes, lack of racial diversity and inconsistent phenotyping. With funding for the parent RO1, we recently published the results of our racially and ethnically diverse 2000 women cohort. This study provides conclusive data that CSTs and specific bacterial taxa are strongly associated with sPTB. Furthermore, we found that local CV immune responses modify the risk of sPTB associated with high-risk CSTs, suggesting that CV microbial-immune profiles are of critical importance for sPTB risk. Providing possible insight into the known racial disparity with sPTB, our data demonstrate that black women are more likely to be colonized with a high-risk CSTs and have differential expression of CV immune mediators that modify the risk of sPTB. While our findings suggest an opportunity for therapeutic interventions to reduce sPTB, recent advances suggest that only by understanding the totality of an ecosystem and the subsequent host response can we have the greatest impact on health and disease. In this proposal, we are uniquely positioned to advance this field with rigor by deciphering the role of the CV microbiota in a large cohort of well-phenotyped sPTB. We are also poised to address disparities by focusing additional studies on black women. These studies will reveal innovative biological mechanisms in sPTB including 1) whether select CSTs are associated with molecular evidence of premature cervical remodeling and 2) whether high-risk CV microbial-immune profiles are present prior to pregnancy and/or does pregnancy shift women to a favorable or unfavorable state. Addressing these gaps in knowledge will provide novel information as to potential new windows for intervention as well as identifying potential modifiers associated with a high-risk CV microbial-immune state which could lead to a reduction of sPTB in black women.